The present invention relates especially to the familial detection of predisposition or susceptibility to prostate cancer, as well as to the possibility of demonstrating the genes responsible for this disease, and the therapeutic strategies derived from this identification.
In France, the rough rate of incidence of prostate cancer is 35/100,000 men. This rate increases regularly by 10/100,000 per decade. In parallel, mortality from prostate cancer progresses: 8234 deaths or 10% of the deaths from cancer in 1986, and 9000 or 11% in 1990. The estimations, in terms of public health, are pessimistic for prostate cancer because of the ageing of the population; this cancer is the 2nd cause of mortality from cancer in man and the 1st in men of more than 70 years.
The study of the natural history of prostate cancers shows that men having prostate cancer on average lose 40% of their life expectancy. At present, the only curative treatments of prostate cancer in its localized (early) form are surgery or radiotherapy, with a recovery rate at 5 years limited to approximately 50%. In order that the mortality rate from this cancer decreases, more localized tumours must be detected because these are, in the state of therapeutics available, the only ones which are curable.
Early diagnosis based on the determination of PSA (prostate specific antigen) appears to be the method today which is most able to contribute to a decrease in mortality from prostate cancer: the rise in the level of PSA will precede clinical detection for the localized forms by approximately 7 years. However, certain reserves have been expressed with respect to the use of the determination of PSA for detecting prostate cancers; in fact, the PSA level is not specific for prostate cancer, but for a pathological attack on this organ, whether it be benign or malignant.
A predictive diagnosis by genetic means must allow the susceptible individuals to benefit from a more early and thus curative treatment, or even from a non-specific chemoprevention (retinoic acid, vitamin D or 5.alpha.-reductase inhibitors) or specific chemoprevention, made practicable from the identification of the genetic bases of the disease.
It is thus important to be able to define with accuracy the populations at risk of prostate cancer in order to be able to apply a rational detection and early diagnosis strategy, on the data of the predictive genotype diagnosis.
However, the risk factors of prostate cancer in general populations are not at present known with certainty.
The incidence of clinical prostate cancer varies according to the countries and the ethnic groups; to explain these variations, genetic and epigenetic factors, have been touched on without it having been possible to incriminate any mesological factor with an absolute significance. The standardized incidence (for 100,000 inhabitants) of clinical prostate cancer is estimated at 35 in France, but the figures vary from 2 in China to 80 for the dark-skinned population in the USA.
No etiological cause of alimentary origin or connected with the environment has been determined with certainty to this date.
Certain genetic polymorphisms are associated with an increased individual risk of specific cancers, and in the case of prostate cancer could explain the significant variations in incidence observed between different populations. A specific polymorphism of the black American populations which have a high risk of prostate cancer has been demonstrated for the gene of the enzyme 5.alpha.-reductase of type 2 (SRD5A2 gene localized in 2p23). The 5.alpha.-reductase of type 2 is an enzyme which transforms testosterone into dihydrotestosterone and which is directly involved in growth and androgendependent prostate differentiation. Independently of the ethnic origin, a specific polymorphism of the gene of the vitamin D receptor (VDR gene localized in 12q12) has been correlated with a risk of developing prostate cancer; it had additionally been suggested that the individuals having a low circulating level of vitamin D were more exposed to prostate cancer.
It is known today that there is a familial risk of prostate cancer. Already, clinical studies in the 1950s had caused a familial aggregation in prostate cancer to be recalled. Control-case clinical studies have been conducted more recently to attempt to evaluate the part of the genetic risk factors. Thus Steinberg et al., 1990, and McWhorter et al., 1992 confirm that the risk of prostate cancer is increased in subjects having one or more relatives already affected by the disease and when forms of early diagnosis in the relatives exist.
It follows from these studies that previous familial histories of prostate cancer are the principal risk factor of prostate cancer. It is thus essential to be able to identify the genetic bases of these susceptibilities or predispositions to prostate cancer in order to be able to target the individuals who can benefit from a diagnosis and a more efficacious treatment.
Genetic analyses (research on loss of heterozygosis and of point mutations) have been conducted in prostate tumours.
It is now well established that cancer is a disease due to the deregulation of the expression of certain genes. In fact, the development of a tumour necessitates an important succession of steps. Each of these steps comprises the deregulation of an important gene intervening in the normal metabolism of the cell and the emergence of an abnormal cellular sub-clone which overwhelms the other cell types because of a proliferative advantage. The genetic origin of this concept has found confirmation in the isolation and the characterization of genes which could be responsible. These genes, commonly called "cancer genes", have an important role in the normal metabolism of the cell and are capable of intervening in carcinogenesis following a change.
The studies of loss of heterozygosis (LOH) in the DNA of tumours and cytogenetic observations have shown that several chromosomal regions were lost in certain prostate cancers. No cytogenetic change, no oncogene, nor specific predisposition gene, however, has yet been identified as specific for prostate cancers (review by Cussenot, 1996). The research is carried out by observation of certain deletions or losses of alleles on cancers in different clinico-pathological stages. Certain of these deleted chromosomal regions are already known to be carriers of suppressor genes of tumours involved in different cancers and thus do not have any specificity in prostate adenocarcinomas (13q-14 and Rb gene, 18q-21 and DCC gene, 16q22 and E-caderine gene, 17q-13 and p53 gene, 17q-12 and BRCAI gene). The KAI1 gene (11p11.2) has been identified for the first time as a suppressor gene of prostate cancer metastasis; this gene is expressed in numerous tissues, it codes for a membrane glycoprotein, and its suppressant function which is restricted to prostate cancers does not remain very probable. The oncogenes and genetic amplifications observed in the prostate cancers would appear to be involved in a late state of the disease, in particular during the escape phase in hormonal treatment.
It thus remains to localize and to identify the genes specifically involved in the development and the progression of prostate cancers starting from the genetic analysis of the hereditary forms and to define their clinical implications in terms of prognosis and therapeutic innovations.